1. Field of the Invention
This invention relates to a process for producing a 1-phosphorylated saccharide derivative. 1-phosphorylated saccharides are—widely distributed in the living world, are reaction substrates for a variety of enzymes and are utilized starting materials for preparing useful substances such as drugs and nutritional foods. Synthetic 1-phosphorylated saccharide derivatives have been expected to be used as starting materials for preparing drugs such as antiviral agents and enzyme inhibitors.
This invention also relates to a process for producing a nucleoside compound used as a starting material or drug substance for medical drugs such as antiviral, anticancer and antisense drugs.
2. Description of the Prior Art
There are known processes for producing a 1-phosphorylated saccharide such as:
1) condensation of a 1-bromosaccharide with a silver phosphate salt (J. Biol. Chem., Vol.121, p.465 (1937); J. Am. Chem. Soc., Vol.78, p.811 (1956); J. Am. Chem. Soc., Vol.79, p.5057 (1957));
2) condensation of a 1-halogenated saccharide with a triethylamine salt of dibenzylphosphoric acid (J. Am. Chem. Soc., Vol.77, p.3423 (1955); J. Am. Chem. Soc., Vol.80, p.1994 (1958); J. Am. Chem. Soc., Vol.106, p.7851 (1984); J. Org. Chem., Vol.59, p.690 (1994));
3) thermal condensation of a 1-acetylated saccharide with orthophosphoric acid (J. Org. Chem., Vol.27, p.1107 (1962); Carbohydrate Res., Vol.3, p.117 (1966); Carbohydrate Res., Vol.3, p.463 (1967); Can. J. Biochem., Vol.50, p.574 (1972));
4) condensation of dibenzylphoshoric acid with a saccharide activated at 1-position by imidation (Carbohydrate Res., Vol.61, p.181 (1978); Tetrahedron Lett., Vol.23, p.405 (1982));
5) treatment of a saccharide activated at 1-position by thallium or lithium alcolate with dibenzylphosphoric chloride (Carbohydrate Res., Vol.94, p.165 (1981); Chem. Lett., Vol.23, p.405 (1982));
6) phosphorolysis of a nucleoside utilizing action of nucleoside phosphorylase to form a 1-phoshorylated saccharide derivative (J. Biol. Chem., Vol.184, p.437 (1980)).
These processes have the following drawbacks.
A common problem in the chemical processes described in the above 1) to 5) is that it is difficult to establish a general synthetic method for preparing a desired isomer with a good selectivity due to variation in an anomer selectivity between α/β anomers owing to influence of a functional group adjacent to 1-position. For achieving selectivity and a good yield, the presence of 2-acetoxy or acetamino group is essential. However, since 2-deoxysaccharide is unstable, these synthetic processes may be limited to a considerably narrow application range. Thus, it is difficult to control anomer selectivity so that column chromatography purification is required, leading to a poor yield (Chem. Zvesti, Vol.28(1), p.115 (1974); Izv. Akad. Nauk SSSR, Ser. Khim., Vol.8, p.1843 (1975)).
Of course, there have been no reports for chemical preparation of a 1-phosphorylated 2-deoxyfuranose which is more unstable than a 1-phosphorylated 2-deoxypyranose, resulting in more difficult selectivity control.
In terms of 6), preparation of a nucleoside itself is difficult except a quite limited type of rebonucleosides such as inosine. A limited type of 1-phosphorylated saccharide derivatives such as ribose-1-phosphate can be, therefore, prepared. In addition, since a nucleoside itself as a starting material is expensive, the process is not satisfactory in its cost.
As described above, the term “nucleoside phosphorylase” is a generic name for enzymes capable of phosphorolysis of an N-glycoside bond in a nucleoside in the presence of phosphoric acid, which catalyze a reaction represented by the following equation:Nucleoside+Phosphoric acid (salt)→Base+1-Phosphorylated saccharide derivative
The enzymes which may be generally categorized into two groups of purine nucleoside phosphorylases and pyrimidine nucleoside phosphorylases, are widely distributed in the living world; they are present in tissues of mammals, birds and fish; yeasts; and bacteria. The enzyme reaction is reversible and there have been disclosed methods for synthesis of a variety of nucleosides utilizing a reverse reaction; for syntheses of thymidine (thymine, adenine or guanine) (JP-A 01-104190), 2′-deoxyadenosine (JP-A 11-137290) or 2′-deoxyguanosine (JP-A 11-137290) from 2′-deoxyribose 1-phosphate and a nucleic-acid base.
Furthermore, Agric. Biol. Chem., Vol.50 (1), pp.121–126 (1986) has described a process where by a reaction using a purine nucleoside phosphorylase from Enterobacter aerogenes in the presence of phosphoric acid, inosine is decomposed into ribose 1-phosphate and hypoxanthine and the former isolated using an ion-exchange resin and 1,2,4-triazole-3-carboxamide are also treated with a purine nucleoside phosphorylase from Enterobacter aerogenes to prepare ribavirin as an antiviral agent.
However, as described above, an industrial process for producing a 1-phosphorylated saccharide derivative has not been established, and thus an industrial process for preparation of a universally useful nucleoside utilizing a reverse reaction of a nucleoside phosphorylase has been also not established.
Furthermore, since the reaction for forming a nucleoside from 1-phosphorylated saccharide derivative and a base utilizing the reverse reaction of the enzyme is reversible, there is a technical drawback that an inversion rate cannot be improved.